Bis-(dihydroxyphenyl-ethylol)-substituted alkylenediamines and the salts thereof

ABSTRACT

Compounds of the formula WHEREIN R1 is hydrogen or methyl, R2 is methyl, methoxy, ethoxy or chlorine and, if R1 is methyl, additionally hydrogen, and M IS A WHOLE NUMBER FROM 0 TO 10, INCLUSIVE, AND THEIR NONTOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS, USEFUL AS BRONCHIAL AND UTERINE SPASMOLYTICS, ANTIPRURITICS, VASODILATORS AND ANTIALLERGICS IN WARM-BLOODED ANIMALS.

United States Patent Schromm et al.

[ 1 June 27, 1972 [54] BlS-(DIHYDROXYPHENYL-ETHYLOL)- SUBSTITUTED ALKYLENEDIAMINES AND THE SALTS THEREOF [72] Inventors: Kurt Schromm; Anton Mentrup; Karl Zeile; Ernst-Otto Renth, all of lngelheim/Rhine; Albrecht Engelhardt, Mainz; Werner Traunecker, Munster-Sarmsheim,

all of Germany [73] Assignee: Boehringer Ingelheim G.m.b.H., lngelheim/Rhine, Germany [22] Filed: Dec. 2, 1969 21 Appl. No.: 881,606

[30] Foreign Application Priority Data Dec. 3, 1968 Austria ..A 11776/68 Nov. 10, 1969 Austria ..A 10533/69 [52] US. Cl. ..260/253, 260/340.5, 260/479 R, 260/50l.l8, 260/570.5 D, 260/570.5 L, 260/592, 424/253, 424/330 [51] Int. Cl. ..C07c 91/22, C07d 57/36 [58] Field of Search ..260/501.l8, 570.6, 253

[56] References Cited UNITED STATES PATENTS 3,329,709 7/1967 Schmid etal. ..260/570.6

Primary Examiner-Robert V. Hines Attorney-Hammond & Littell [5 7] ABSTRACT Compounds of the formula HO R2 OH Ilia Iii HO HCH2-NH(|](CH:)m(fNHCHz- R2 OH wherein R, is hydrogen or methyl,

R is methyl, methoxy, ethoxy or chlorine and, if R is methyl, additionally hydrogen, and l m is a whole number from 0 to 10, inclusive, and their nontoxic, pharmacologically acceptable acid addition salts, useful as bronchial and uterine spasmolytics, antipruritics, vasodilators and antiallergics in warm-blooded animals.

9 Claims, No Drawings 3,673,187 1 2 BlS-(DIHYDROXYPHENYL-ETHYLOL)-SUBSTITUTED with hydrochloric acid, hydrobromic acid, sulfuric acid, ALKYLENEDIAMINESAND'I'HESALTS THEREOF phosphoric acid, acetic acid, citric acid, tartaric acid, 8-

Thi invention relat t novel N,N'-bi dihydroxyphenyp chlorotheophylline or the like. Such acid addition salts are obethylol)-alkylenediamines and acid addition salts thereof, as 5 mined y customaly methods, Such as y acidifying a Solution well as to methods of preparing th oompounds of the free base with the desired inorganic or organic acid.

More particularly, the present invention relates to com- The following examples further illustrate the l ihveh pounds of the formula tion and enable others skilled in the artto understand it R2 H I H0 H2 v I I'll l (1)11 H0 GH0HOH -HN(p-(cHz)m?-NHCHzCH- -0H v .51. l wherein Q 5 more completely. It should be understood, however, that the 1 is hydrogen methyl, invention is not limited solely to the particular examples given R is methyl, 'methoxy, ethoxy or chlorine and, if R, is b l methyl, additionally hydrogen, and m is an integer from 0 to 10, inclusive, and their non-toxic, EXAMPLE 1 pharmacologically acceptable acid addition salts, in the a I form of pure stereoisomers, mixtures of stereoisomers or N,N'-Bis-[,B(3',4'-dihydroxy-phenyl)-B-hydroxy-ethyl]-l ,4-

racemates. butylenediamine dihydrochloride I A compound of the formula I may be prepared by methods A mixture consisting of 270 gm of 2,3,4-trihydroxyinvolving well known chemical principles, namely, by reducacetophenone [prepared pursuant to Org. Synth. 14, 40 ing a compound of the formula 1934)]772 of acetone, 131 ml of pyridine and 338 grri of RO R2 R2 0R i i i RO- GCH2NR"-fiJ-(CHz)m(fNR"CH2 C 0R I R1 R1 (II) wherein R,, R and m have the same meanings as in formula diphenyl-dichloro-methane was allowed to stand overnight at R is hydrogen or a protective group which is easily removable room temperature, and then a olution of 200 gm of sodium by hydrolysis or hydrogenation, preferably benzyl, acyl or, h d id i 500 l f water wa added in small portions. The together Whh each other and the adjacent yg atoms, an reaction solution was allowed to stand for 2 hours at room 206ml radical, Qh as diphehylmethylehedioxy, and is temperature and was then acidified with concentrated hydrogen h y hydrochloric acid. The crystalline slurry formed thereby was The Eduction y be effected elthel' y catalytw vacuum-filtered, and the filter cake was washed first with hydrogenation using the customary platinum, palladium or water and then with methanol. 249 gm f the 2 3 4 Raney nickel catalysts, or with the aid of complex hydrrdes, 40 diphenyhnethylenedioxy acetophenone 155L15 C) such as sodium borohydride or lithium aluminum hydride; or thus obmined were reacted at with 288 m1 of di th l also by means of the Meerwein-Ponndorf-Verle Reducnon sulfate and 204 gm of potassium hydroxide in methanolic solu- (alummum alkoflde reducuon) tion. The precipitated reaction product was collected and ad- If the prolecuve groups axe not already 5pm off dunng the mixed with ether, the mixture was vacuum-filtered, and the filreduction, they may subsequently be removed by customary Hate was evaporated The 2 methoxy 3 d methods.

. 1 methylenedloxy-acetophenone obtained thereby was A Starting compound of the formula H may be obt for brominated at 80 C. in benzene solution. The solution was example by reacting a compound of the formula evaporated, and the raw a-bromo-2-methoxy-3,4 diphenyl- I R2 methylenedioxyacetophenone thus obtained was recrystal- 0 lizedfrom isopropanol(m. p. 137C). 42.5 gm of this bromoketone were admixed with 26.8 gm of I N,N'-dibenzyl-1,4-butylenediamine and 400 ml of acetone,

and the mixture was refluxed. Thereafter, the reaction mixture wherein R2 has the same meanings as in formula has the was vacuum-filtered, the filtrate was acidified with ethereal same meanings as in formula II, and X is chlorine or bromine hydrochloric acid, and water was added to the acidic solution with an alkylenediamine of the formula hegah to become yy [l 3 ,4-d1phenylmethylenedioxy-2 '-methoxy-phenyl )-}3oxoethyl]-l,4-butylenediamine dihydrochloride precipitated out;

f" p a after recrystallization from acetonitrile it had a melting point [1N R"C(0I'I2)mCNR"H of l96l98 C. 15 gm of this compound were boiled for 90 I I (IV) minutes with a mixture consisting of 88.5 ml of methanol and p 61.5 ml of concentrated hydrochloric acid, and the reaction wherein R 'and m have the same meanings as in formula I, and solution was allowed to cool, whereupon N,N'-dibenzyl-N,N-

R" has the same meanings as in formula 11-, in the presence of -[34 y y-2'- y-p y M hy la condensation agent, such as potassium carbonate, or of an --butylenediamine dihydrochloride P- from excess of diamine IV abov the t i hj i amount water/ethanol) precipitated out. The precipitate was collected required for reaction with compound Ill. and then hydrogenated in a mixture of methanol and water I (3:1) at 60 C. and 5 atmospheres pressure in the presence of Racemic mixtures of the compounds of the formula I may, be separated into their individual stereoisomeric components palladized charcoal as a catalyst, yielding N,N'-bis-[B-(2'- by customary methods. methoxy-3',4'-dihydroxy-phenyl)-B-oxo-ethyl]-1,4-bu- The bis-substituted alkylenediamines represented by forrnutylenediamine dihydrochloride [ms p. 235-236 C. la 1 are organic bases and therefore form acid addition salts (decomp), from water/acetonitrile]. with inorganic or organic acids. Examples of non-toxic, phar- This diketone was then hydrogenated in methanol at room macologically acceptable acid addition salts are those formed temperature. and atmospheric pressure in' the presence of 3 platinum as a catalyst, whereby N,N'-bis-[B-( 2'-methoxy-3 ,4-dihydroxy-phenyl ]-B-hydroxy-ethyl 1 ,4-butylenediamine dihydrochloride of the formula methanol/acetonitrile, the product had a melting point of 173-174 C.

EXAMPLEZ N ,N -Bis-[B-( 2' -ethoxy-3 ,4 -dihydroxy-phenyl -B-hydroxyethyl]-l ,4-butylenediamine dihydrochloride Analogous to Example 1, a-bromo-2-ethoxy-3,4-diphenylmethylenedioxy-acetophenone '(m. p. 6365 C.) was prepared from 2-ethoxy-3,4-diphenylrnethylenedioxyacetophenone (m. p. 84-87 C.). 47.5 gm of the bromoketone, together with 14.5 gm of N,N'-dibenzyl-l,4-butylenediamine and 15 gm of sodium carbonate were refluxed in ethanol for 3 hours. Thereafter, the reaction mixture was vacuum-filtered, and the filtrate was evaporated. The residue was dissolved in 300 ml of methanol, the solution was acidified with ethereal hydrochloric acid, and the acidic solution was hydrogenated at 60 C. and atmospheres pressure in the presence of palladized charcoal as a catalyst, yielding N,N'- bis-[ ,B-( 2'-ethoxy-3 ,4'-diphenylmethylenedioxy-phenyl )-fioxo-ethylI-l ,4-butylenediamine dihydrochloride which had a melting point'of 208-2l0 C. after recrystallization from acetonitrile.

By boiling 23 gm of this product for 1% hours in admixture with 140 ml of methanol and 90 ml of concentrated hydrochloric acid and thereafter distilling off the methanol, N ,N-bis-[B-( 2-ethoxy-3 ,4-dihydroxy-phenyl )-B-oxoethyl]-l ,4-butylenediamine dihydrochloride (m. p. 227-230 C., from water/acetonitrile) was obtained. This compound was hydrogenated at room temperature and atmospheric pressure in methanol in the presence of platinum as a catalyst.

After completion of the hydrogenation, the catalyst was filtered off, the filtrate was evaporated, and the residue was recrystallized from ethanol, yielding N,N-bis-[B-(2'-ethoxy- 3 ,4-dihydroxy-phenyl )-fi-hydroxy-ethyl]- l ,4-butylenediamine dihydrochloride, m. p. l80-182C., of the for- EXAMPLE 3 hours. Thereafter, the reaction mixture was vacuum-filtered, the filtrate was evaporated, the residue was dissolved in 300 ml of methanol, the solution was acidified with ethereal HO CH3 formula which had a melting point of l88-189 C. after recrystallization from water/acetone.

EXAMPLE 4 N,N-Bis- [B-( 2 -methoxy-3 ,4-dihydroxy-phenyl )-B-hydroxyethyl} l ,6-hexylenediamine dihydrochloride A mixture consisting of 42.5 gm of a-bromo-2-methoxy-3,4- diphenylmethylenedioxy-acetophenone (for preparation see Example 1), 14.8 gm of N,N'-dibenzyl-l,6-hexylenediamine, 15 gm of sodium carbonate, 200ml of ethanol and 75 ml of acetonitrile was refluxed for 3 hours. Thereafter, the reaction mixture was vacuum-filtered, the filtrate was evaporated, the residue was dissolved in 300 ml of methanol, the solution was acidified with ethereal hydrochloric acid, and the acidic solution was hydrogenated at 60 C. and 5 atmospheres pressure in the presence of palladized charcoal. After completion of the hydrogenation the catalyst was vacuum-filtered off, the filtrate was evaporated, and the residual N,N'-bis-[B-(2'-methoxy-3 ,4'-diphenylmethylenedioxy-phenyl )-fi-oxo-ethyl l ,6-hexylenediamine, m. p. 218222 C. (decomp.), was crystallized from acetonitrile.

A mixture of 19 gm of this crystalline product, 78 ml of concentrated hydrochloric acid and 112 ml of methanol was refluxed for minutes and yielded N,N-bis-[B-(2-methoxy- 3 ,4'-dihydroxy-phenyl )-B-oxo-ethyl]- 1 ,6-hexylenediamine dihydrochloride (m. p. 258-259 C., from water), which was hydrogenated in methanol at room temperature and atmospheric pressure in the presence of platinum as a catalyst. After completion of the hydrogenation the catalyst was vacuum-filtered off, and the methanol was evaporated, whereby N,N'-bis-[B-( 2-methoxy-3 ,4'-dihydroxy-phenyl )-B- hydroxy-ethyll-l,6-hexylenediamine dihydrochloride of the formula H0 OCH3 CHaO 9H was obtained which had a melting point of l76l 78 C. after recrystallization from water/isopropanol.

EXAMPLE 5 N,N-Bis-[ ,B-( 2'-methoxy-3 ,4-dihydroxy-phenyl )-B-hydroxy- 5 ethyl l ,8-diamino-octane dihydrochloride Using a procedure analogous to that described in Example 4, N,N'-bis-[B-( 2-methoxy-3 ,4'-dihydroxy-phenyl )-/3- hydroxy-ethyl]-l ,8-diamino-octane dihydrochloride, m. p. 12 ll24 C. (from ethanol/ether), of the formula .H O CH3 EXAMPLE 6 yethyl]-2,5-dimethyl-2,S-diamino-hexane dihydrochloride A mixture consisting of 100 gm of a-bromo-3,4-di-methoxy- 2-methyl-acetophenone (m.p. 87-89 C, prepared by brominating 3,4-dimethoxy-2-methyl-acetophenone in' ether), 26.5 gm of 2,S-dimethyl-2,5-diamino-hexane, 300 ml of ethanol and 55 gm of sodium carbonate was refluxed for 3 hours. Thereafter, the reaction mixture was vacuum filtered, the filtrate was evaporated, the residue was dissolved in 300 ml of ether, and the solution was extracted twice with water, dried with sodium sulfate and evaporated. The oily residue was dissolved in 150 ml of acetonitrile, the resulting solution was acidified with ethereal hydrochloric acid, and the N,N- bis-[,B-( 3 ,4 -dimethoxy-Z-methyl-phenyl )-,B-oxoethyl ]-2 ,5- dimethyl-2,5-diamino-hexane dihydrochloride precipitated thereby was collected and recrystallized from water, whereupon it had a melting point of 2l32l7 C. This product was boiled with 48 percent hydrobromic acid, yielding N,N-bis-[B 3 ,4-dihydroxy-2'-methyl-phenyl )-B-oxo-ethyl ]-2,5- dimethyl-2,S-diamino-hexane dihydrobromide, which was converted into the free base by treatment with aqueous ammonia and subsequently into the dihydrochloride (m.p. 220-230 C) with ethereal hydrochloric acid. Catalytic hydrogenation of this dihydrochloride in methanol at room temperature and atmospheric pressure in the presence of platinum as a catalyst yielded N,N'-bis-[B-(2-methyl-3',4'- dihydroxy-phenyl)-,B-hydroxy-ethyl]-2,5-dimethyl-2,5- diamino-hexane dihydrochloride, m.p. 176l78 C, of the formula HO CH3 l CH:

EXAMPLE 7 benzyloxy-acetophenone [m.p. 92 C, prepared by brominating 3,4-dibenzyloxy-acetophenone (m.p. 9697 C, in benzene at 50f C)], 7.2 gm of 2,5-dimethyl-2,5-diaminohexane, 15 gm of sodium carbonate, 200 ml of ethanol and 20 ml of acetonitrile was refluxed for 4 hours. Thereafter, the reaction mixture was vacuum-filtered, the filtrate was evaporated, the residue was dissolved in 100 ml of ether, and the resulting solution was extracted twice with 100 ml of water, dried with sodium sulfate and evaporated. The residue was dissolved in 50 ml of acetonitrile, the resulting solution was acidified with ethereal hydrochloric acid, and the N,N- bis-[ ,8-( 3 ,3 '-dibenzyloxy-phenyl )-,8-oxo-ethyl ]-2,5-dimethyl- 2,5-diamino-hexane dihydrochloride precipitated thereby was collected and recrystallized from ethylacetate/ether,whereupon it had a melting point of 22122'6 C. The dihydrochloride was converted into the free base with dilute ammonia, the base was dissolved in 300 ml of ethanol,-and the solution was reduced with sodium borohydride, whereby N,N '-bis-[,B-( 3 ',4'-dibenzyloxy-phenyl )-,8-hydroxy-ethyl ]-2,5 -dimethyl-2,S-diamino-hexane gradually precipitated out. The free base was dissolved in acetonitrile, the solution was acidified with ethereal hydrochloric acid, and the dihydrochloride (m.p. 202-205 C) was precipitated by addition of water to the acidic solution. The dihydrochloride was collected and catalytically hydrogenated in methanol in the presence of palladized charcoal at room temperature and atmospheric pressure, yielding N,N-bis-[B-(3,4-dihydroxyphenyl)-fi-hydroxy-ethyl] -2,5-dimethyl-2,S-diamino-hexane dihydrochloride of the formula which had a melting point of 228C after recrystallization from water/acetonitrile.

EXAMPLE 8 was dissolved in a mixture of ethanol and dioxane, and the solution was reduced with sodium borohydride to yield N,N- bis-[B-(2'-chloro-3',4'-benzyloxy'phenyl)-B-hydroxy;ethyl]- 1,6-diamino-hexane, which was converted into its dihydrochloride (m.p. 98-103 C) in acetonitrileethylacetate solution by means of ethereal hydrochloric acid. The dihydrochloride was catalytically hydrogenated under standard conditions in the presence of Raney nickel as a catalyst, yielding N,N -bis-[,B-(2'-chloro-3',4'-dihydroxyphenyl )-B-hydroxy-ethyl] l ,o-diamino-hexane dihydrochloride of the formula which had a melting point of 190l93 C after recrystallization from water/acetone.

The compounds according to the present invention, i.e., those embraced by formula 1 above and their non-toxic, pharmacologically acceptable acid addition salts, have useful pharmacodynamic properties. More particularly, they exhibit'longlasting broncho-spasmolytic activities in warm-blooded animals without, at the same time, producing the undesirable side-effects especially undesirable effects upon theheart usually produced by known broncho-spasmolytics of related structure, such as N,N'-bis-[/3-( 3,4'-dihydroxy-phenyl )-/3- hydroxy-ethyl]-alkylenediamines. In addition, the compounds according to the present invention produce a spasmolytic action upon the uterus and also exhibit antipruritic, vasodilating and antiallergic activities in warm-blooded animals.

For pharmaceutical purposes the compounds according to the present invention are administered to warm-blooded animals perorally, parenterally or topically as active ingredients in customary pharmaceutical compositions, that is, compositions consisting essentially of an inert pharmaceutical carrier and an effective amount of the active ingredient, such as tablets, coated pills, capsules, aerosols, ointments, tinctures or solutions.

One effective dosage unit of the compounds of the present invention for oral administration is from 0.083 to 0.84 mgm/kg.

Their effective concentration for topical administration is from 0.1 to 5 percent, based on the total weight of the topical composition.

The effective unit dosage for parenteral administration is 0.083 to 1.67 'y/kg.

Finally, the effective concentration for inhalation aerosol compositions is 0.1 to 5 percent, based on the total weight of the aerosol.

The following examples illustrate a few pharmaceutical compositions comprising a compound of the instant invention as an active ingredients, and represent the best mode contemplated of putting the invention to practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 9 Tablets The tablet composition was compounded from the following ingredients:

butane dihydrochloride 20.0 parts Stearic acid 6.0 parts Dextrose 574.0 parts Total 600.0 parts EXAMPLE l0 Ointment The ointment was compounded from the following ingredients:

hexane dihydrochloride 0200 parts Fuming hydrochloric acid 0.01 1 parts Sodium pyrosulfate 0.050 parts Mixture of equal parts by volume of cetyl alcohol and stearyl alcohol 18.000 parts White Vaseline 5.000 parts Synthetic bergamot oil 0.075 parts Distilled water q.s.ad 100.000 parts Compounding procedure:

The individual ingredients were admixed and processed in customary fashion-into an ointment. Topically applied,vthe ointment was an effective antipruritic.

pound in illustrative Examples 9 to l 1. Likewise, the amount of active ingredient in these examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that our invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim: 1. A racemic or optically active compound of the formula (1)11 Elli 1 HO OHCH2NI-I(IJ(CHz)m(IJ- R: O H pH NH-CH2- 0H/ 011 wherein R is hydrogen or methyl,

R is methyl, methoxy, ethoxy or chlorine and, if R, is

methyl, also hydrogen, and

m is an integer from 2 to 6, inclusive, or a non-toxic, pharmacologically acceptable acid addition salt thereof.

2. A compound according to claim 1, which is N,N'-bis-[B- (2-methoxy-3 ,4'-dihydroxy-phenyl)-B-hydroxy-ethyl]-l ,4- diamino-butane or a non-toxic, pharmacologically acceptable acid addition salt thereof.

3. A compound according to claim I, which is N,N-bis-[B- (2'-ethoxy-3,4'-dihydroxy-phenyl )-,B-hydroxy-ethyl l ,4- diamino-butane or a non-toxic, pharmacologically acceptable acid addition salt thereof.

4. A compound according to claim 1, which is N,N-bis-[B- (2-methyl-3,4'-dihydroxy-phenyl)-fl-hydroxy-ethyl]-l ,4- diamino-butane or a non-toxic, pharmacologically acceptable acid addition salt thereof.

5. A compound according to claim 1, which is N,N'-bis-[B- (2-methoxy-3 ,4-dihydroxy-phenyl )-B-hydroxy-ethyl]- l ,6- diamino-hexane or a non-toxic, pharmacologically acceptable acid addition salt thereof.

6. A compound according to claim 1, which is N,N-bis-[B- (2'-methoxy-3',4-dihydroxy-phenyl )-fi-hydroxy-ethyl l ,8- diamino-octane or a non-toxic, pharmacologically acceptable acid addition salt thereof.

7. A compound according to claim 1, which is N ,N'-bis-[B- (2-methyl-3',4'-dihydroxy-phenyl)-B-hydroxy-ethyl]-2,5- dimethyl-Z,S-diamino-hexane or a non-toxic, pharmacologically acceptable acid addition salt thereof.

8. A compound according to claim 1, which is N,N-bis-[B- (3 ',4B-hydroxy-ethyl ]-2,5 -dimethyl-2,5- diamino-hexane or a non-toxic, pharmacologically acceptable acid addition salt thereof.

9. A compound according to claim 1, which is N,N-bis-[B- (2-chloro-3 ,4'-dihydroxy-phenyl )-B-hydroxy-ethyl l ,6-

diamino-hexane or a non-toxic, pharmacologically acceptable acid addition salt thereof.

EXAMPLE 1 I Inhalation aerosol The aerosol composition was compounded from the following ingredients:

2,5diaminohexane dihydrochloride 0.20 parts Soybean lecithin 0.05 parts Propellent gas mixture (trichlorofluoromethane, dichlorodifluoromethane and cryofluorane) q.s.ad lO0.00 parts Compounding procedure:

The ingredients were admixed and filled under pressure or deeprefrigeration into an aerosol container provided with a metering valve, which released an amount of aerosol spray b on hoa olyti ff t containing about 1.0 mgm Of the diaminohexane comp und Analogous results were obtained when an equal amount of each time it was actuated. One metered dose of this spray, inany h r o ound of th r nt in ention was sub titut d baled into the p tract of adult Warm-blooded for the particular diaminobutane resp. diaminohexane comanimal, in need of such treatment, produced very goodwag-3" UNITED STATED 'I'AI'ENI' Uranu v CERTIFICATE OF CORRECTION Patent No. 3 73, 7 Dated June 27, 1972 KURT SCHROMM, ANTON MEN-TRUP, KARL ZEILE, ERNST-5T1, O RENTH, ALBRECHT ENGELHARDT and WERNER TRAUNECKER Inventor(s It is eertified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

001. 4,- line 66, c'orrect the formula to read HO CHOH-CH2-HN4-(CH2)6NH-CH2- Col. 5, line 13, correct the formula to read HO OCH3 Col. 6, line 34, in ther-iormula correct CH h to read CH i- I I CH- c C01. 8, line after "35 4' insert -dihydroxy-pheqy1)- L Signed and sealed this 13th day of March 1973 J (SEAL) Attest: v

EDWARD M.FLETCHER,JR. ROBERT GOTTSCIIALK Attesting Officer I v v Commissioner of Patents 

2. A compound according to claim 1, which is N,N''-bis-( Beta -(2''-methoxy-3'',4''-dihydroxy-phenyl)- Beta -hydroxy-ethyl)-1,4-diamino-butane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 3. A compound according to claim 1, which is N,N''-bis-( Beta -(2''-ethoxy-3'',4''-dihydroxy-phenyl)- Beta -hydroxy-ethyl)-1,4-diamino-butane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 4. A compound according to claim 1, which is N,N''-bis-( Beta -(2''-methyl-3'',4''-dihydroxy-phenyl)- Beta -hydroxy-ethyl)-1,4-diamino-butane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 5. A compound according to claim 1, which is N,N''-bis-( Beta -(2''-methoxy-3'',4''-dihydroxy-phenyl)- Beta -hydroxy-ethyl)-1,6-diamino-hexane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 6. A compound according to claim 1, which is N,N''-bis-( Beta -(2''-methoxy-3'',4''-dihydroxy-phenyl)- Beta -hydroxy-ethyl)-1,8-diamino-octane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 7. A compound according to claim 1, which is N,N''-bis-( Beta -(2''-methyl-3'',4''-dihydroxy-phenyl)- Beta -hydroxy-ethyl)-2,5-dimethyl-2,5-diamino-hexane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 8. A compound according to claim 1, which is N,N''-bis-( Beta -(3'',4''-dihydroxy-phenyl)- Beta -hydroxy-ethyl)-2,5-dimethyl-2,5-diamino-hexane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 9. A compound according to claim 1, which is N,N''-bis-( Beta -(2''-chloro-3'',4''-dihydroxy-phenyl)- Beta -hydroxy-ethyl)-1,6-diamino-hexane or a non-toxic, pharmacologically acceptable acid addition salt thereof. 